Imperial College London
Alternate

ProfessorSimakAli

Faculty of Medicine, Department of Surgery & Cancer

Professor of Molecular Endocrine Oncology
 
 
 
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Contact

 

+44 (0)20 7594 2811simak.ali

 
 
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Location

 

133ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Flach:2020:10.1158/0008-5472.CAN-19-2207,
author = {Flach, KD and Periyasamy, M and Jadhav, A and Dorjsuren, D and Siefert, JC and Hickey, TE and Opdam, M and Patel, H and Canisius, S and Wilson, DM and Collier, MD and Prekovic, S and Nieuwland, M and Kluin, RJC and Zakharov, A and Wesseling, J and Wessels, LFA and Linn, SC and Tilley, WD and Simeonov, A and Ali, S and Zwart, W},
doi = {10.1158/0008-5472.CAN-19-2207},
journal = {Cancer Research},
pages = {1914--1926},
title = {Endonuclease FEN1 coregulates ER alpha activity and provides a novel drug interface in tamoxifen-resistant breast cancer},
url = {http://dx.doi.org/10.1158/0008-5472.CAN-19-2207},
volume = {80},
year = {2020}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Estrogen receptor α (ERα) is a key transcriptional regulator in the majority of breast cancers. ERα-positive patients are frequently treated with tamoxifen, but resistance is common. In this study, we refined a previously identified 111-gene outcome prediction-classifier, revealing FEN1 as the strongest determining factor in ERα-positive patient prognostication. FEN1 levels were predictive of outcome in tamoxifen-treated patients, and FEN1 played a causal role in ERα-driven cell growth. FEN1 impacted the transcriptional activity of ERα by facilitating coactivator recruitment to the ERα transcriptional complex. FEN1 blockade induced proteasome-mediated degradation of activated ERα, resulting in loss of ERα-driven gene expression and eradicated tumor cell proliferation. Finally, a high-throughput 465,195 compound screen identified a novel FEN1 inhibitor, which effectively blocked ERα function and inhibited proliferation of tamoxifen-resistant cell lines as well as ex vivo–cultured ERα-positive breast tumors. Collectively, these results provide therapeutic proof of principle for FEN1 blockade in tamoxifen-resistant breast cancer.
AU  - Flach,KD
AU  - Periyasamy,M
AU  - Jadhav,A
AU  - Dorjsuren,D
AU  - Siefert,JC
AU  - Hickey,TE
AU  - Opdam,M
AU  - Patel,H
AU  - Canisius,S
AU  - Wilson,DM
AU  - Collier,MD
AU  - Prekovic,S
AU  - Nieuwland,M
AU  - Kluin,RJC
AU  - Zakharov,A
AU  - Wesseling,J
AU  - Wessels,LFA
AU  - Linn,SC
AU  - Tilley,WD
AU  - Simeonov,A
AU  - Ali,S
AU  - Zwart,W
DO  - 10.1158/0008-5472.CAN-19-2207
EP  - 1926
PY  - 2020///
SN  - 0008-5472
SP  - 1914
TI  - Endonuclease FEN1 coregulates ER alpha activity and provides a novel drug interface in tamoxifen-resistant breast cancer
T2  - Cancer Research
UR  - http://dx.doi.org/10.1158/0008-5472.CAN-19-2207
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000535265800009&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - https://cancerres.aacrjournals.org/content/80/10/1914
UR  - http://hdl.handle.net/10044/1/80921
VL  - 80
ER  -
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